The general objective of this proposed renewal for an ADRC at Columbia University is to foster innovative research on AD and related disorders, both locally in our extensive campus and more globally with other institutions and organizations. Informed by the funding opportunity announcement and influenced by recent advancements, a general theme of this renewal is better defining normal aging and the transition from normal aging to the earliest stages of AD. Since its inception 24 years ago, the ADRC at Columbia has established an elaborate infrastructure for research, fostered interdisciplinary collaborations, established a rich training environment, and promoted outreach and patient recruitment. At the same time the ADRC has become an active participant in a more global network comprised of other institutions, national consortia, and community organizations. During its latest cycle, the ADRC has attained most of its goals and its success is evidenced, for example, by the breadth of its scientific achievements and by its #1 ranking in the number of enrolled and active patients. In this proposed renewal, our ADRC will build off of these prior accomplishments moving forward, and will be motivated by two general goals. The first broad goal is to continue, as in previous cycles, to foster innovative research on AD and related disorders, while the second more specific goal is to support the theme of this cycle. These goals will be accomplished via a number of specific aims, which include: 1) Supporting and integrating the cores and other resources to facilitate research on AD and related disorders. 2) Fostering and expanding our multidisciplinary and multi-department local network at Columbia University with a focus on better understanding the relationship between aging and AD. 3) Fostering and expanding our participation in a global network outside of Columbia University, by playing active roles in national efforts and consortia that collect clinical, genetic, and neuroimaging data, as well as biospecimens. 4) Supporting the development of new techniques and methodologies, particularly in delineating the transition from aging to AD, and supporting the translation of thes findings into better diagnostic, prevention and treatment strategies. 5) Fostering and expanding education and outreach to patients, particularly individuals in the earliest stages of disease, and in the training of young and new investigators. The cores provide the structural backbone of our ADRC. As evidenced by the success of the cores during the previous cycle the same cores and their leaders will be part of this renewal, thereby assuring smooth continuity and the promise of future success. Besides the Administrative Core, these cores include: A Clinical Core led by Dr. Larry Honig; a Data Management and Statistical Core led by Dr. Howard Andrews; a Neuropathology Core led by Dr. Jean-Paul Vonsattel; a Human Genetics Core led by Dr. Richard Mayeux; and, an Outreach, Retention, and Education Core led by Dr. Karen Bell. The specific projects allow the ADRC to mobilize towards its scientific goals, and towards its expansionist goals of fostering new science, investigators, and careers. In this proposed renewal the ADRC will support three new projects, all led by new investigators. Dr. Adam Brickman will lead Project 1 entitled, Hippocampal circuitry and white matter abnormalities in aging and AD. Drs. Sandra Barral and Christiane Reitz will co-lead Project 2 entitled, Genetic variations linked to the aging hippocampus. Dr. John Crary will lead Project 3 entitled, Post- transcriptional regulation of tau in aging and AD.